Taxanes having a C10 carbamoyloxy substituent

ABSTRACT

Taxanes having a carbamoyloxy substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and side chain substituents.

REFERENCE TO RELATED APPLICAION

This application is a continuation of application Ser. No. 09/775,852filed Feb. 2, 2001 now U.S. Pat. No. 6,596,737.

This application claims priority from U.S. provisional application Ser.No. 60/179,793, filed on Feb. 2, 2000.

BACKGROUND OF THE INVENTION

The present invention is directed to novel taxanes which haveexceptional utility as antitumor agents.

The taxane family of terpenes, of which baccatin III and taxol aremembers, has been the subject of considerable interest in both thebiological and chemical arts. Taxol itself is employed as a cancerchemotherapeutic agent and possesses a broad range of tumor-inhibitingactivity. Taxol has a 2′R, 3′S configuration and the followingstructural formula:

wherein Ac is acetyl.

Colin et al. reported in U.S. Pat. No. 4,814,470 that certain taxolanalogs have an activity significantly greater than that of taxol. Oneof these analogs, commonly referred to as docetaxel, has the followingstructural formula:

Although taxol and docetaxel are useful chemotherapeutic agents, thereare limitations on their effectiveness, including limited efficacyagainst certain types of cancers and toxicity to subjects whenadministered at various doses. Accordingly, a need remains foradditional chemotherapeutic agents with improved efficacy and lesstoxicity.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof taxanes which compare favorably to taxol and docetaxel with respectto efficacy as anti-tumor agents and with respect to toxicity. Ingeneral, these taxanes possess a carbamoyloxy substituent at C-10, ahydroxy substituent at C-7 and a range of C-3′ substituents.

Briefly, therefore, the present invention is directed to the taxanecomposition, per se, to pharmaceutical compositions comprising thetaxane and a pharmaceutically acceptable carrier, and to methods ofadministration.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment of the present invention, the taxanes of the presentinvention correspond to structure (1):

wherein

R₂ is acyloxy;

R₇ is hydroxy;

R₉ is keto, hydroxy, or acyloxy;

R₁₀ is carbamoyloxy;

R₁₄ is hydrido or hydroxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl orheterocyclo;

X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

Ac is acetyl; and

R₇, R₉, and R₁₀ independently have the alpha or beta stereochemicalconfiguration.

In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate(R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbonate(R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferredembodiment, R₂ is an ester (R_(2a)C(O)O—)a wherein R_(2a) is aryl orheteroaromatic. In another preferred embodiment, R₂ is an ester(R_(2a)C(O)O—), wherein R_(2a) is substituted or unsubstituted phenyl,furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂is benzoyloxy.

While R₉ is keto in one embodiment of the present invention, in otherembodiments R₉ may have the alpha or beta stereochemical configuration,preferably the beta stereochemical configuration, and may be, forexample, α- or β-hydroxy or α- or β-acyloxy. For example, when R₉ isacyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate(R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O)O—), or a thiocarbonate(R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester(R_(9a)C(O)O—), R_(9a) is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaromatic. Still more preferably,R₉ is an ester (R_(9a)C(O)O—), wherein R_(9a) is substituted orunsubstituted phenyl, substituted or unsubstituted furyl, substituted orunsubstituted thienyl, or substituted or unsubstituted pyridyl. In oneembodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl, (straight, branched or cyclic), or hexyl (straight, branched orcyclic). In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) issubstituted methyl, substituted ethyl, substituted propyl (straight,branched or cyclic), substituted butyl (straight, branched or cyclic),substituted pentyl, (straight, branched or cyclic), or substituted hexyl(straight, branched or cyclic) wherein the substituent(s) is/areselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties, but notphosphorous containing moieties.

In one embodiment, R₁₀ is R_(10a)R_(10b)NCOO— wherein R_(10a) andR_(10b) are indpendently hydrogen, hydrocarbyl, substituted hydrocarbylor heterocyclo. Exemplary preferred R₁₀ substituents includeR_(10a)R_(10b)NCOO— wherein (a) R_(10a) and R_(10b) are each hydrogen,(b) one of R_(10a) and R_(10b) is hydrogen and the other is (i)substituted or unsubstituted C₁ to C₈ alkyl such as methyl, ethyl, orstraight, branched or cyclic propyl, butyl, pentyl, or hexyl; (ii)substituted or unsubstituted C₂ to C₈ alkenyl such as ethenyl orstraight, branched or cyclic propenyl, butenyl, pentenyl or hexenyl;(iii) substituted or unsubstituted C₂ to C₈ alkynyl such as ethynyl orstraight or branched propynyl, butynyl, pentynyl, or hexynyl; (iv)substituted or unsubstituted phenyl, or (v) substituted or unsubstitutedheteroaromatic such as furyl, thienyl, or pyridyl, or (c) R_(10a) andR_(10b) are independently (i) substituted or unsubstituted C₁ to C₈alkyl such as methyl, ethyl, or straight, branched or cyclic propyl,butyl, pentyl, or hexyl; (ii) substituted or unsubstituted C₂ to C₈alkenyl such as ethenyl or straight, branched or cyclic propenyl,butenyl, pentenyl or hexenyl; (iii) substituted or unsubstituted C₂ toC₈ alkynyl such as ethynyl or straight or branched propynyl, butynyl,pentynyl, or hexynyl; (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl. The substituents may be those identified elsewhere herein forsubstituted hydrocarbyl. In one embodiment, preferred R₁₀ substituentsinclude R_(10a)R_(10b)NCOO— wherein one of R_(10a) and R_(10b) ishydrogen and the other is methyl, ethyl, or straight, branched or cyclicpropyl.

Exemplary X₃ substituents include substituted or unsubstituted C₂ to C₈alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substituted orunsubstituted C₂ to C₈ alkynyl, substituted or unsubstitutedheteroaromatics containing 5 or 6 ring atoms, and substituted orunsubstituted phenyl. Exemplary preferred X₃ substituents includesubstituted or unsubstituted ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀ whereinX₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl orheteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀,—COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₁to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl (straight, branched or cyclic), or hexyl (straight, branched orcyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such assubstituted or unsubstituted ethenyl, propenyl (straight, branched orcyclic), butenyl (straight, branched or cyclic), pentenyl (straight,branched or cyclic) or hexenyl (straight, branched or cyclic); (iii)substituted or unsubstituted C₂ to C₈ alkynyl such as substituted orunsubstituted ethynyl, propynyl (straight or branched), butynyl(straight or branched), pentynyl (straight or branched), or hexynyl(straight or branched); (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl, wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

In one embodiment of the present invention, the taxanes of the presentinvention correspond to structure (2):

wherein

R₇ is hydroxy;

R₁₀ is carbamoyloxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, orheterocyclo, wherein alkyl comprises at least two carbon atoms;

X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

For example, in this preferred embodiment in which the taxanecorresponds to structure (2), R₁₀ may be R_(10a)R_(10b)NCOO— wherein oneof R_(10a) and R_(10b) is hydrogen and the other is (i) substituted orunsubstituted C₁ to C₈ alkyl such as methyl, ethyl, or straight,branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted orunsubstituted C₂ to C₈ alkenyl such as ethenyl or straight, branched orcyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted orunsubstituted C₂ to C₈ alkynyl such as ethynyl or straight or branchedpropynyl, butynyl, pentynyl, or hexynyl; (iv) phenyl or substitutedphenyl such as nitro, alkoxy or halosubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl. The substituents may be those identified elsewhere herein forsubstituted hydrocarbyl. In one embodiment, preferred R₁₀ substituentsinclude R_(10a)R_(10b)NCOO— wherein one of R_(10a) and R_(10b) ishydrogen and the other is substituted or unsubstituted, preferablyunsubstituted methyl, ethyl, or straight, branched or cyclic propyl. Inanother embodiment, preferred R₁₀ substituents includeR_(10a)R_(10b)NCOO— wherein one of R_(10a) and R_(10b) is hydrogen andthe other is substituted or unsubstituted phenyl or heterocyclo. WhileR_(10a) and R_(10b) are selected from among these, in one embodiment X₃is selected from substituted or unsubstituted alkyl, alkenyl, phenyl orheterocyclo, more preferably substituted or unsubstituted alkenyl,phenyl or heterocyclo, still more preferably substituted orunsubstituted phenyl or heterocyclo, and still more preferablyheterocyclo such as furyl, thienyl or pyridyl. While R_(10a), R_(10b),and X₃ are selected from among these, in one embodiment X₅ is selectedfrom —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, more preferablyphenyl. Alternatively, while R_(10a), R_(10b), and X₃ are selected fromamong these, in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ isphenyl, alkyl or heterocyclo, more preferably phenyl, or X₅ is —COOX₁₀wherein X₁₀ is alkyl, preferably t-butyl. Among the more preferredembodiments, therefore, are taxanes corresponding to structure 2 inwhich (i) X₅ is —COOX₁₀ wherein X₁₀ is tert-butyl or X₅ is —COX₁₀wherein X₁₀ is phenyl, (ii) X₃ is substituted or unsubstitutedcycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substitutedor unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, stillmore preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and(iii) R₁₀ is R_(10a)R_(10b)NCOO—, one of R_(10a) and R_(10b) is hydrogenand the other is substituted or unsubstituted substituted orunsubstituted C₁ to C₈ alkyl, phenyl or heterocyclo.

Among the preferred embodiments, therefore, are taxanes corresponding tostructure 1 or 2 wherein R₁₀ is R_(10a)R_(10b)NCOO— wherein R_(10a) ismethyl and R_(10b) is hydrido. In this embodiment, X₃ is preferablycycloalkyl, isobutenyl, phenyl, substituted phenyl such asp-nitrophenyl, or heterocyclo, more preferably heterocyclo, still morepreferably furyl, thienyl or pyridyl; and X₅ is preferably benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydroxy. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydrido. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydrido. In each of the alternativesof this embodiment when the taxane has structure 1, R₇ and R₁₀ may eachhave the beta stereochemical configuration, R₇ and R₁₀ may each have thealpha stereochemical configuration, R₇ may have the alpha stereochemicalconfiguration while R₁₀ has the beta stereochemical configuration or R₇may have the beta stereochemical configuration while R₁₀ has the alphastereochemical configuration.

Also among the preferred embodiments are taxanes corresponding tostructure 1 or 2 wherein R₁₀ is R_(10a)R_(10b)NCOO— wherein R_(10a) isethyl and R_(10b) is hydrido. In this embodiment, X₃ is preferablycycloalkyl, isobutenyl, phenyl, substituted phenyl such asp-nitrophenyl, or heterocyclo, more preferably heterocyclo, still morepreferably furyl, thienyl or pyridyl; and X₅ is preferably benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl. In one alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydrido. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is keto and R₁₄ is hydroxy. In another alternative of thisembodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is hydroxy and R₁₄ is hydrido. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydroxy. In another alternative ofthis embodiment, X₃ is heterocyclo; X₅ is benzoyl, alkoxycarbonyl, orheterocyclocarbonyl, more preferably benzoyl, t-butoxycarbonyl ort-amyloxycarbonyl, still more preferably t-butoxycarbonyl; R₂ isbenzoyl, R₉ is acyloxy and R₁₄ is hydrido. In each of the alternativesof this embodiment when the taxane has structure 1, R₇ and R₁₀ may eachhave the beta stereochemical configuration, R₇ and R₁₀ may each have thealpha stereochemical configuration, R₇ may have the alpha stereochemicalconfiguration while R₁₀ has the beta stereochemical configuration or R₇may have the beta stereochemical configuration while R₁₀ has the alphastereochemical configuration.

Taxanes having the general formula 1 may be obtained by carbamoylationof a suitably protected taxane intermediate having the structuralformula:

wherein X₃ and X₅ are as previously defined, P₂ is a hydroxy protectinggroup, and P₇ is either hydrogen or a hydroxy protecting group, byreaction with an isocyanate or a carbamoyl chloride, followed by removalof the hydroxy protecting group(s).

The intermediate taxane may be obtained by treatment of a β-lactam withan alkoxide having the taxane tetracyclic nucleus and a C-13 metallicoxide substituent to form compounds having a β-amido ester substituentat C-13 (as described more fully in Holton U.S. Pat. No. 5,466,834),followed by removal of either the C(10) protecting group, or both theC(10) and C(7) protecting groups. The β-lactam has the formula (3):

wherein P₂ is a hydroxy protecting group and X₃ and X₅ are as previouslydefined and the alkoxide has the formula (4):

wherein M is a metal or ammonium, and P₇ and P₁₀ are hydroxy protectinggroups.

The alkoxide may be prepared from 10-deacetylbaccatin III by protectionof the C-7 and C-10 hydroxyl groups (as described more fully in Holtonet al., PCT Patent Application WO 99/09021) followed by treatment with ametallic amide.

Derivatives of 10-deacetylbaccatin III having alternative substituentsat C(2), C(9) and C(14) and processes for their preparation are known inthe art. Taxane derivatives having acyloxy substituents other thanbenzoyloxy at C(2) may be prepared, for example, as described in Holtonet al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat. No.6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) inplace of keto may be prepared, for example as described in Holton etal., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No.5,352,806. Taxanes having a beta hydroxy substituent at C(14) may beprepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.Processes for the preparation and resolution of the β-lactam startingmaterial are generally well known. For example, the β-lactam may beprepared as described in Holton, U.S. Pat. No. 5,430,160 and theresulting enatiomeric mixtures of β-lactams may be resolved by astereoselective hydrolysis using a lipase or enzyme as described, forexample, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614or a liver homogenate as described, for example, in PCT PatentApplication No. 00/41204. In a preferred embodiment in which theβ-lactam is furyl substituted at the C(4) position, the β-lactam can beprepared as illustrated in the following reaction scheme:

wherein Ac is acetyl, NEt₃ is triethylamine, CAN is ceric ammoniumnitrate, and p-TsOH is p-toluenesulfonic acid. The beef liver resolutionmay be carried out, for example, by combining the enatiomeric β-lactammixture with a beef liver suspension (prepared, for example, by adding20 g of frozen beef liver to a blender and then adding a pH 8 buffer tomake a total volume of 1 L).

Compounds of formula 1 of the instant invention are useful forinhibiting tumor growth in mammals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of a compound of the instant invention incombination with at least one pharmaceutically or pharmacologicallyacceptable carrier. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of theantitumor compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the antitumor compounds ofthe present invention may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the invention can be formulated for any route ofadministration so long as the target tissue is available via that route.Suitable routes of administration include, but are not limited to, oral,parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal), topical (nasal, transdermal,intraocular), intravesical, intrathecal, enteral, pulmonary,intralymphatic, intracavital, vaginal, transurethral, intradermal,aural, intramammary, buccal, orthotopic, intratracheal, intralesional,percutaneous, endoscopical, transmucosal, sublingual and intestinaladministration.

Pharmaceutically acceptable carriers for use in the compositions of thepresent invention are well known to those of ordinary skill in the artand are selected based upon a number of factors: the particularantitumor compound used, and its concentration, stability and intendedbioavailability; the disease, disorder or condition being treated withthe composition; the subject, its age, size and general condition; andthe route of administration. Suitable carriers are readily determined byone of ordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp. 1492-1517, the contents of which areincorporated herein by reference).

The compositions are preferably formulated as tablets, dispersiblepowders, pills, capsules, gelcaps, caplets, gels, liposomes, granules,solutions, suspensions, emulsions, syrups, elixirs, troches, dragees,lozenges, or any other dosage form which can be administered orally.Techniques and compositions for making oral dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the invention for oral administration comprise aneffective antitumor amount of a compound of the invention in apharmaceutically acceptable carrier. Suitable carriers for solid dosageforms include sugars, starches, and other conventional substancesincluding lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar,mannitol, sorbitol, calcium phosphate, calcium carbonate, sodiumcarbonate, kaolin, alginic acid, acacia, corn starch, potato starch,sodium saccharin, magnesium carbonate, tragacanth, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, talc,magnesium stearate, and stearic acid. Further, such solid dosage formsmay be uncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

The antitumor compounds of the present invention are also preferablyformulated for parenteral administration, e.g., formulated for injectionvia intravenous, intraarterial, subcutaneous, rectal, subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective antitumoramount of the antitumor compound in a pharmaceutically acceptablecarrier. Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions or any other dosage formwhich can be administered parenterally. Techniques and compositions formaking parenteral dosage forms are known in the art.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1, 3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide amides,2-pyrrolidinone, 1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone);esters (e.g., 1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esterssuch as monoacetin, diacetin, and triacetin, aliphatic or aromaticesters such as ethyl caprylate or octanoate, alkyl oleate, benzylbenzoate, benzyl acetate, dimethylsulfoxide (DMSO), esters of glycerinsuch as mono, di, or tri-glyceryl citrates or tartrates, ethyl benzoate,ethyl acetate, ethyl carbonate, ethyl lactate, ethyl oleate, fatty acidesters of sorbitan, fatty acid derived PEG esters, glycerylmonostearate, glyceride esters such as mono, di, or tri-glycerides,fatty acid esters such as isopropyl myristrate, fatty acid derived PEGesters such as PEG-hydroxyoleate and PEG-hydroxystearate, N-methylpyrrolidinone, pluronic 60, polyoxyethylene sorbitol oleic polyesterssuch as poly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄,poly(oxyethylene)₁₅₋₂₀ monooleate, poly(oxyethylene)₁₅₋₂₀ mono12-hydroxystearate, and poly(oxyethylene)₁₅₋₂₀ mono ricinoleate,polyoxyethylene sorbitan esters such as polyoxyethylene-sorbitanmonooleate, polyoxyethylene-sorbitan monopalmitate,polyoxyethylene-sorbitan monolaurate, polyoxyethylene-sorbitanmonostearate, and Polysorbate® 20, 40, 60 or 80 from ICI Americas,Wilmington, Del., polyvinylpyrrolidone, alkyleneoxy modified fatty acidesters such as polyoxyl 40 hydrogenated castor oil and polyoxyethylatedcastor oils (e.g., Cremophor® EL solution or Cremophor® RH 40 solution),saccharide fatty acid esters (i.e., the condensation product of amonosaccharide (e.g., pentoses such as ribose, ribulose, arabinose,xylose, lyxose and xylulose, hexoses such as glucose, fructose,galactose, mannose and sorbose, trioses, tetroses, heptoses, andoctoses), disaccharide (e.g., sucrose, maltose, lactose and trehalose)or oligosaccharide or mixture thereof with a C₄-C₂₂ fatty acid(s)(e.g.,saturated fatty acids such as caprylic acid, capric acid, lauric acid,myristic acid, palmitic acid and stearic acid, and unsaturated fattyacids such as palmitoleic acid, oleic acid, elaidic acid, erucic acidand linoleic acid)), or steroidal esters); alkyl, aryl, or cyclic ethershaving 2-30 carbon atoms (e.g., diethyl ether, tetrahydrofuran, dimethylisosorbide, diethylene glycol monoethyl ether); glycofurol(tetrahydrofurfuryl alcohol polyethylene glycol ether); ketones having3-30 carbon atoms (e.g., acetone, methyl ethyl ketone, methyl isobutylketone); aliphatic, cycloaliphatic or aromatic hydrocarbons having 4-30carbon atoms (e.g., benzene, cyclohexane, dichloromethane, dioxolanes,hexane, n-decane, n-dodecane, n-hexane, sulfolane, tetramethylenesulfon,tetramethylenesulfoxide, toluene, dimethylsulfoxide (DMSO), ortetramethylenesulfoxide); oils of mineral, vegetable, animal, essentialor synthetic origin (e.g., mineral oils such as aliphatic or wax-basedhydrocarbons, aromatic hydrocarbons, mixed aliphatic and aromatic basedhydrocarbons, and refined paraffin oil, vegetable oils such as linseed,tung, safflower, soybean, castor, cottonseed, groundnut, rapeseed,coconut, palm, olive, corn, corn germ, sesame, persic and peanut oil andglycerides such as mono-, di- or triglycerides, animal oils such asfish, marine, sperm, cod-liver, haliver, squalene, squalane, and sharkliver oil, oleic oils, and polyoxyethylated castor oil); alkyl or arylhalides having 1-30 carbon atoms and optionally more than one halogensubstituent; methylene chloride; monoethanolamine; petroleum benzin;trolamine; omega-3 polyunsaturated fatty acids (e.g., alpha-linolenicacid, eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoicacid); polyglycol ester of 12-hydroxystearic acid and polyethyleneglycol (Solutol® HS-15, from BASF, Ludwigshafen, Germany);polyoxyethylene glycerol; sodium laurate; sodium oleate; or sorbitanmonooleate.

Other pharmaceutically acceptable solvents for use in the invention arewell known to those of ordinary skill in the art, and are identified inThe Chemotherapy Source Book (Williams & Wilkens Publishing), TheHandbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, PA, 1995),The United States Pharmacopeia 24, The National Formulary 19, (NationalPublishing, Philadelphia, Pa., 2000), A. J. Spiegel et al., and Use ofNonaqueous Solvents in Parenteral Products, JOURNAL OF PHARMACEUTICALSCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include those known to stabilize the antitumorcompounds, such as oils rich in triglycerides, for example, saffloweroil, soybean oil or mixtures thereof, and alkyleneoxy modified fattyacid esters such as polyoxyl 40 hydrogenated castor oil andpolyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor®RH 40 solution). Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid ® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®. Ethanol is a preferred solvent for use in dissolving theantitumor compound to form solutions, emulsions, and the like.

Additional minor components can be included in the compositions of theinvention for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the antitumor compound at the site ofadministration, protect the stability of the composition, control thepH, facilitate processing of the antitumor compound into pharmaceuticalformulations, and the like. Preferably, each of these components isindividually present in less than about 15 weight % of the totalcomposition, more preferably less than about 5 weight %, and mostpreferably less than about 0.5 weight % of the total composition. Somecomponents, such as fillers or diluents, can constitute up to 90 wt. %of the total composition, as is well known in the formulation art. Suchadditives include cryoprotective agents for preventing reprecipitationof the taxane, surface active, wetting or emulsifying agents (e.g.,lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylenestearate), preservatives (e.g., ethyl-p-hydroxybenzoate), microbialpreservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol,sorbic acid, thimerosal and paraben), agents for adjusting pH orbuffering agents (e.g., acids, bases, sodium acetate, sorbitanmonolaurate), agents for adjusting osmolarity (e.g., glycerin),thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol,stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes,flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g.,bentonites), adhesives, bulking agents, flavorings, sweeteners,adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, orsorbitol, cellulose, or calcium phosphate), diluents (e.g., water,saline, electrolyte solutions), binders (e.g., starches such as maizestarch, wheat starch, rice starch, or potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers,acacia), disintegrating agents (e.g., starches such as maize starch,wheat starch, rice starch, potato starch, or carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereofsuch as sodium alginate, croscarmellose sodium or crospovidone),lubricants (e.g., silica, talc, stearic acid or salts thereof such asmagnesium stearate, or polyethylene glycol), coating agents (e.g.,concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide),and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodiumsulfite, dextrose, phenols, and thiophenols).

In a preferred embodiment, a pharmaceutical composition of the inventioncomprises at least one nonaqueous, pharmaceutically acceptable solventand an antitumor compound having a solubility in ethanol of at leastabout 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not beingbound to a particular theory, it is believed that the ethanol solubilityof the antitumor compound may be directly related to its efficacy. Theantitumor compound can also be capable of being crystallized from asolution. In other words, a crystalline antitumor compound, such ascompound 1393, can be dissolved in a solvent to form a solution and thenrecrystallized upon evaporation of the solvent without the formation ofany amorphous antitumor compound. It is also preferred that theantitumor compound have an ID50 value (i.e, the drug concentrationproducing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8,9, or 10 times less that of paclitaxel when measured according to theprotocol set forth in the working examples.

Dosage form administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Dosage and regimens for the administration of the pharmaceuticalcompositions of the invention can be readily determined by those withordinary skill in treating cancer. It is understood that the dosage ofthe antitumor compounds will be dependent upon the age, sex, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired. For any mode ofadministration, the actual amount of antitumor compound delivered, aswell as the dosing schedule necessary to achieve the advantageouseffects described herein, will also depend, in part, on such factors asthe bioavailability of the antitumor compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present inventionshould be sufficient to effect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the antitumor compound, whether administered orally or by anotherroute, is any amount which would result in a desired therapeuticresponse when administered by that route. Preferably, the compositionsfor oral administration are prepared in such a way that a single dose inone or more oral preparations contains at least 20 mg of the antitumorcompound per m² of patient body surface area, or at least 50, 100, 150,200, 300, 400, or 500 mg of the antitumor compound per m² of patientbody surface area, wherein the average body surface area for a human is1.8 m². Preferably, a single dose of a composition for oraladministration contains from about 20 to about 600 mg of the antitumorcompound per m² of patient body surface area, more preferably from about25 to about 400 mg/m² even more preferably, from about 40 to about 300mg/m², and even more preferably from about 50 to about 200 mg/m².Preferably, the compositions for parenteral administration are preparedin such a way that a single dose contains at least 20 mg of theantitumor compound per m² of patient body surface area, or at least 40,50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m²of patient body surface area. Preferably, a single dose in one or moreparenteral preparations contains from about 20 to about 500 mg of theantitumor compound per m² of patient body surface area, more preferablyfrom about 40 to about 400 mg/m²′ and even more preferably, from about60 to about 350 mg/m². However, the dosage may vary depending on thedosing schedule which can be adjusted as necessary to achieve thedesired therapeutic effect. It should be noted that the ranges ofeffective doses provided herein are not intended to limit the inventionand represent preferred dose ranges. The most preferred dosage will betailored to the individual subject, as is understood and determinable byone of ordinary skill in the art without undue experimentation.

The concentration of the antitumor compound in a liquid pharmaceuticalcomposition is preferably between about 0.01 mg and about 10 mg per mlof the composition, more preferably between about 0.1 mg and about 7 mgper ml, even more preferably between about 0.5 mg and about 5 mg per ml,and most preferably between about 1.5 mg and about 4 mg per ml.Relatively low concentrations are generally preferred because theantitumor compound is most soluble in the solution at lowconcentrations. The concentration of the antitumor compound in a solidpharmaceutical composition for oral administration is preferably betweenabout 5 weight % and about 50 weight %, based on the total weight of thecomposition, more preferably between about 8 weight % and about 40weight %, and most preferably between about 10 weight % and about 30weight %.

In one embodiment, solutions for oral administration are prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® EL solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution for oraladministration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving an antitumor compound in any pharmaceuticallyacceptable solvent capable of dissolving the compound (e.g.,ethanol ormethylene chloride) to form a solution. The solvent can optionally becapable of evaporating when the solution is dried under vacuum. Anadditional carrier can be added to the solution prior to drying, such asCremophor® EL solution. The resulting solution is dried under vacuum toform a glass. The glass is then mixed with a binder to form a powder.The powder can be mixed with fillers or other conventional tablettingagents and processed to form a tablet for oral administration to apatient. The powder can also be added to any liquid carrier as describedabove to form a solution, emulsion, suspension or the like for oraladministration.

Emulsions for parenteral administration can be prepared by dissolving anantitumor compound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas Liposyn® II or Liposyn® III emulsion, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient. If desired, such emulsions can beformulated to contain a minimal amount of, or to be free of, ethanol orCremophor® solution, which are known in the art to cause adversephysiological effects when administered at certain concentrations inparenteral formulations.

Solutions for parenteral administration can be prepared by dissolving anantitumor compound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas Cremophor® solution, is added to the solution while stirring to forma pharmaceutically acceptable solution for parenteral administration toa patient. If desired, such solutions can be formulated to contain aminimal amount of, or to be free of, ethanol or Cremophor® solution,which are known in the art to cause adverse physiological effects whenadministered at certain concentrations in parenteral formulations.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable taxane concentration prior to use as is known in the art.

Definitions

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

The term “heteroaromatic” as used herein alone or as part of anothergroup denote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may bebonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R isR¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

Unless otherwise indicated, the alkoxycarbonyloxy moieties describedherein comprise lower hydrocarbon or substituted hydrocarbon orsubstituted hydrocarbon moieties.

Unless otherwise indicated, the carbamoyloxy moieties described hereinare derivatives of carbamic acid in which one or both of the aminehydrogens is optionally replaced by a hydrocarbyl, substitutedhydrocarbyl or heterocyclo moiety.

The terms “hydroxyl protecting group” and “hydroxy protecting group” asused herein denote a group capable of protecting a free hydroxyl group(“protected hydroxyl”) which, subsequent to the reaction for whichprotection is employed, may be removed without disturbing the remainderof the molecule. A variety of protecting groups for the hydroxyl groupand the synthesis thereof may be found in “Protective Groups in OrganicSynthesis” by T. W. Greene, John Wiley and Sons, 1981, or Fieser &Fieser. Exemplary hydroxyl protecting groups include methoxymethyl,1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl,tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and2,2,2-trichloroethoxymethyl.

As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” means ethyl;“Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl; “tBu” and“t-Bu” means tert-butyl; “R” means lower alkyl unless otherwise defined;“py” means pyridine or pyridyl; “TES” means triethylsilyl; “TMS” meanstrimethylsilyl; “LAH” means lithium aluminum hydride; “10-DAB” means10-desacetylbaccatin III”; “amine protecting group” includes, but is notlimited to, carbamates, for example, 2,2,2-trichloroethylcarbamate ortertbutylcarbamate; “protected hydroxy” means—OP wherein P is a hydroxyprotecting group; “tBuOCO” and “Boc” mean tert-butoxycarbonyl; “tAmOCO”means tert-amyloxycarbonyl; “2-FuCO” means 2-furylcarbonyl; “2-ThCO”means 2-thienylcarbonyl; “2-PyCO” means 2-pyridylcarbonyl; “3-PyCO”means 3-pyridylcarbonyl; “4-PyCO” means 4-pyridylcarbonyl; “C₄H₇CO”means butenylcarbonyl; “EtOCO” means ethoxycarbonyl; “ibueCO” meansisobutenylcarbonyl; “iBuCO” means isobutylcarbonyl; “iBuOCO” meansisobutoxycarbonyl; “iPrOCO” means isopropyloxycarbonyl; “nPrOCO” meansn-propyloxycarbonyl; “nPrCO” means n-propylcarbonyl; “ibue” meansisobutenyl; “THF” means tetrahydrofuran; “DMAP” means 4-dimethylaminopyridine; “LHMDS” means Lithium HexamethylDiSilazanide.

The following examples illustrate the invention.

EXAMPLE 1

7,10-(bis)-carbobenzyloxy-10-deacetyl baccatin III. To a solution of10-DAB (1.14 g, 2.11 mmol) in 20 mL of methylene chloride was added DMAP(6.20 g, 50.6 mmol) and benzyl chloroformate (1.8 mL, 12.7 mmol) slowlyunder a nitrogen atmosphere. The mixture was heated to 40-45° C., keptat this temperature for 2 h, and an additional 1.8 mL (12.7 mmol) ofbenzyl chloroformate was added. Heating at 40-45° C. was continued foran additional 6 h, the mixture was diluted with 200 mL of CH₂Cl₂ andwashed three times first with 1N HCl and then with saturated sodiumbicarbonate solution. The combined washings were extracted three timeswith 30 mL of CH₂Cl₂, the organic layers were combined, washed withbrine, dried over Na₂SO₄, and concentrated under reduced pressure.Chromatography of the residue on silica gel eluting with CH₂Cl₂/EtOAcgave 1.48 g (86%) of 7,10-(bis)-carbobenzyloxy-10-deacetyl baccatin III.

7,10-(bis)-carbobenzyloxy-3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel. To a solution of 425 mg (0.523 mmol) of7,10-(bis)-carbobenzyloxy-10-deacetyl baccatin III in THF (4.5 mL) at−45° C. under a nitrogen atmosphere was added 0.80 mL of a solution ofLHMDS (0.98 M) in THF dropwise. The mixture was kept at −45° C. for 1 hprior to addition of a solution of 341 mg (0.889 mmol) ofcis-N-tbutoxycarbonyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one in2 mL of THF. The mixture was allowed to warm to 0° C., and after 2 h waspoured into 20 mL of saturated ammonium chloride solution. The aqueouslayer was extracted three times with 50 mL of EtOAc/Hexanes (1:1) andthe organic layers were combined, washed with brine, dried over Na₂SO₄and concentrated. Chromatography of the residue on silica gel elutingwith EtOAc/Hexanes gave 576 mg (92%) of7,10-(bis)-carbobenzyloxy-3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel.

3′-Desphenyl-3′-(2-thienyl)-2′-O-triethylsilyl docetaxel. A suspensionof 550 mg of7,10-(bis)-carbobenzyloxy-3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel and 50 mg of 10% Pd/C in 30 mL of EtOH and 10 mL of EtOAc wasstirred under a hydrogen atmosphere for 2 h at room temperature. Theslurry was filtered through a pad of celite 545 which was then washedwith EtOAc. The washings were concentrated and the residue was purifiedby column chromatography on silica gel using EtOAc/Hexanes as eluent togive 405 mg (95%) of 3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel.

3′-Desphenyl-3′-(2-thienyl)-2′-O-triethylsilyi-10-N-ethylcarbamoyldocetaxel. To a slurry of 3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyldocetaxel (201 mg, 0.217 mmol) and CuCl (43.0 mg, 0.434 mmol) in THF(3.5 mL) at −15° C. under a nitrogen atmosphere was added a solution of51.5 mL (0.651 mmol) of ethyl isocynate in 1.9 mL of THF. The mixturewas warmed to 0° C. and after 1.4 h 5mL of saturated aqueous sodiumbicarbonate solution and 20 mL of ethyl acetate were added. The waterlayer was extracted three times with 50 mL of EtOAc/Hexanes (1:1). Theorganic layers were combined, dried over Na₂SO₄ and evaporated to give218 mg of a residue which was used directly without purification.

3′-D sphenyl-3′-(2-thienyl)-10-N— thylcarbamoyl docetaxel (2722). To asolution of the 218 mg of3′-desphenyl-3′-(2-thienyl)-2′-O-triethylsilyl-10-N-ethylcarbamoyldocetaxel obtained above in 6 mL of pyridine and 12 mL of CH₃CN at 0° C.was added 1.0 mL of 49% aqueous HF. The mixture was warmed to roomtemperature and after 2.5 h 50 mL of EtOAc was added. The mixture waswashed with saturated aqueous sodium bicarbonate solution and brine,dried over sodium sulfate, and concentrated under reduced pressure.Chromatography of the residue on silica gel using CH₂Cl₂/MeOH as eluentgave 169 mg (88% for 2 steps) of3′-desphenyl-3′-(2-thienyl)-10-N-ethylcarbamoyl docetaxel (2722).

EXAMPLE 2

The procedures described in Example 1 were repeated, but other suitablyprotected β-lactams and acylating agents were substituted for theβ-lactam and acylating agent of Example 1 to prepare the series ofcompounds having the combination of substituents identified in thefollowing table. The following table also includes characterization datafor certain of these compounds, along with characterization data for thecompound (2722) prepared in Example 1.

No. X₃ m.p. (° C.) [α]_(D)(CHCl₃) Elemental Analysis 2600 2-pyridyl173-175 −71.4 (c 0.22) Found: C, 60.70; H, 6.69 (Calcd. forC₄₅H₅₇N₃O₁₅.0.5H₂O: C, 60.79; H, 6.58) 2616 3-pyridyl 183-185 −61.0 (c0.20) Found: C, 58.96; H, 6.51 (Calcd. for C₄₅H₅₇N₃O₁₅.2H₂O: C, 59.00;H, 6.69) 2622 3-thienyl 173-175 −68.1 (c 0.19) Found: C, 58.40; H, 6.42(Calcd. for C₄₄H₅₆N₂O₁₅S.H₂O: C, 58.47; H, 6.47) 2633 i-propyl 170-172−75.7 (c 0.22) Found: C, 60.10; H, 7.15 (Calcd. for C₄₃H₆₀N₂O₁₅.H₂O: C,59.84; H, 7.24) 2686 i-butenyl 167-169 −106.7 (c 0.17)  Found: C, 61.12;H, 7.10 (Calcd. for C₄₄H₆₀N₂O₁₅.0.5H₂O: C, 61.02; H, 7.10) 26924-pyridyl 203-205 −69.7 (c 0.18) Found: C, 60.19; H, 6.61 (Calcd. forC₄₅H₅₇N₃O₁₅.H₂O: C, 60.13; H, 6.62) 2700 2-furyl 169-171 −73.6 (C 0.22)Found: C, 60.59; H, 6.58 (Calcd. for C₄₄H₅₆N₂O₁₆: C, 60.82; H, 6.50)2717 3-furyl 165-167 −53.8 (c 0.23) Found: C, 60.07; H, 6.48 (Calcd. forC₄₄H₅₆N₂O₁₆.0.5H₂O: C, 60.14; H, 6.54) 2722 2-thienyl 166-168 −52.2 (c0.25) Found: C, 58.28; H, 6.32 (Calcd. for C₄₄H₅₆N₂O₁₅S.H₂O: C, 58.47;H, 6.47) 2733 cyclobutyl 168-170 −73.9 (c 0.23) Found: C, 60.96; H, 7.02(Calcd. for C₄₄H₆₀N₂O₁₅0.5H₂O: C, 61.02; H, 7.10) 2757 cyclopropyl168-170 −91.7 (c 0.23) Found: C, 60.07; H, 6.86 (Calcd. forC₄₃H₅₅N₂O₁₅.H₂O: C, 59.98; H, 7.02)

EXAMPLE 3

The procedures described in Example 1 were repeated, but other suitablyprotected β-lactams and were substituted for thecis-N-tbutoxycarbonyl-3-triethylsilyloxy-4-(2-thienyl) azetidin-2-one ofExample 1 to prepare the series of compounds corresponding to structure14 and having the combination of substituents identified in thefollowing table.

(14) Compound X₅ X₃ R₁₀ 2640 tBuOCO— phenyl EtNHCOO— 2743 tBuOCO—p-nitrophenyl EtNHCOO— 6015 tC₃H₅CO— 2-furyl 3,4diFPhNHCOO— 6024tC₃H₅CO— 2-furyl PhNHCOO— 6072 tC₃H₅CO— 2-furyl EtNHCOO—

EXAMPLE 4

Following the processes described in Example 1 and elsewhere herein, thefollowing specific taxanes having structural formula 14 and thecombinations of substituents identified in the following table may beprepared, wherein R₁₀ is as previously defined including wherein R₁₀ isR_(10a)R_(10b)NCOO— and (a) R_(10a) and R_(10b) are each hydrogen, (b)one of R_(10a) and R_(10b) is hydrogen and the other is (i) substitutedor unsubstituted C₁ to C₈ alkyl such as methyl, ethyl, or straight,branched or cyclic propyl, butyl, pentyl, or hexyl; (ii) substituted orunsubstituted C₃ to C₈ alkenyl such as ethenyl or straight, branched orcyclic propenyl, butenyl, pentenyl or hexenyl; (iii) substituted orunsubstituted C₃ to C₈ alkynyl such as ethynyl or straight or branchedpropynyl, butynyl, pentynyl, or hexynyl; (iv) substituted orunsubstituted phenyl, or (v) substituted or unsubstituted heteroaromaticsuch as furyl, thienyl, or pyridyl, or (c) R_(10a) and R_(10b) areindependently (i) substituted or unsubstituted C₁ to C₈ alkyl such asmethyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, orhexyl; (ii) substituted or unsubstituted C₂ to C₈ alkenyl such asethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl orhexenyl; (iii) substituted or unsubstituted C₂ to C₈ alkynyl such asethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl;(iv) substituted or unsubstituted phenyl, or (v) substituted orunsubstituted heteroaromatic such as furyl, thienyl, or pyridyl. Forexample, R₁₀ may be R_(10a)R_(10b)NCOO— wherein one of R_(10a) andR_(10b) is hydrogen and the other is methyl, ethyl, or straight,branched or cyclic propyl. The substituents may be those identifiedelsewhere herein for substituted hydrocarbyl.

(14) X₅ X₃ R₁₀ tBuOCO 2-furyl R_(10a)R_(10b)NCOO— tBuOCO 3-furylR_(10a)R_(10b)NCOO— tBuOCO 2-thienyl R_(10a)R_(10b)NCOO— tBuOCO3-thienyl R_(10a)R_(10b)NCOO— tBuOCO 2-pyridyl R_(10a)R_(10b)NCOO—tBuOCO 3-pyridyl R_(10a)R_(10b)NCOO— tBuOCO 4-pyridylR_(10a)R_(10b)NCOO— tBuOCO isobutenyl R_(10a)R_(10b)NCOO— tBuOCOisopropyl R_(10a)R_(10b)NCOO— tBuOCO cyclopropyl R_(10a)R_(10b)NCOO—tBuOCO cyclobutyl R_(10a)R_(10b)NCOO— tBuOCO cyclopentylR_(10a)R_(10b)NCOO— tBuOCO phenyl R_(10a)R_(10b)NCOO— benzoyl 2-furylR_(10a)R_(10b)NCOO— benzoyl 3-furyl R_(10a)R_(10b)NCOO— benzoyl2-thienyl R_(10a)R_(10b)NCOO— benzoyl 3-thienyl R_(10a)R_(10b)NCOO—benzoyl 2-pyridyl R_(10a)R_(10b)NCOO— benzoyl 3-pyridylR_(10a)R_(10b)NCOO— benzoyl 4-pyridyl R_(10a)R_(10b)NCOO— benzoylisobutenyl R_(10a)R_(10b)NCOO— benzoyl isopropyl R_(10a)R_(10b)NCOO—benzoyl cyclopropyl R_(10a)R_(10b)NCOO— benzoyl cyclobutylR_(10a)R_(10b)NCOO— benzoyl cyclopentyl R_(10a)R_(10b)NCOO— benzoylphenyl R_(10a)R_(10b)NCOO— 2-FuCO— 2-furyl R_(10a)R_(10b)NCOO— 2-FuCO—3-furyl R_(10a)R_(10b)NCOO— 2-FuCO— 2-thienyl R_(10a)R_(10b)NCOO—2-FuCO— 3-thienyl R_(10a)R_(10b)NCOO— 2-FuCO— 2-pyridylR_(10a)R_(10b)NCOO— 2-FuCO— 3-pyridyl R_(10a)R_(10b)NCOO— 2-FuCO—4-pyridyl R_(10a)R_(10b)NCOO— 2-FuCO— isobutenyl R_(10a)R_(10b)NCOO—2-FuCO— isopropyl R_(10a)R_(10b)NCOO— 2-FuCO— cyclopropylR_(10a)R_(10b)NCOO— 2-FuCO— cyclobutyl R_(10a)R_(10b)NCOO— 2-FuCO—cyclopentyl R_(10a)R_(10b)NCOO— 2-FuCO— phenyl R_(10a)R_(10b)NCOO—2-ThCO— 2-furyl R_(10a)R_(10b)NCOO— 2-ThCO— 3-furyl R_(10a)R_(10b)NCOO—2-ThCO— 2-thienyl R_(10a)R_(10b)NCOO— 2-ThCO— 3-thienylR_(10a)R_(10b)NCOO— 2-ThCO— 2-pyridyl R_(10a)R_(10b)NCOO— 2-ThCO—3-pyridyl R_(10a)R_(10b)NCOO— 2-ThCO— 4-pyridyl R_(10a)R_(10b)NCOO—2-ThCO— isobutenyl R_(10a)R_(10b)NCOO— 2-ThCO— isopropylR_(10a)R_(10b)NCOO— 2-ThCO— cyclopropyl R_(10a)R_(10b)NCOO— 2-ThCO—cyclobutyl R_(10a)R_(10b)NCOO— 2-ThCO— cyclopentyl R_(10a)R_(10b)NCOO—2-ThCO— phenyl R_(10a)R_(10b)NCOO— 2-PyCO— 2-furyl R_(10a)R_(10b)NCOO—2-PyCO— 3-furyl R_(10a)R_(10b)NCOO— 2-PyCO— 2-thienylR_(10a)R_(10b)NCOO— 2-PyCO— 3-thienyl R_(10a)R_(10b)NCOO— 2-PyCO—2-pyridyl R_(10a)R_(10b)NCOO— 2-PyCO— 3-pyridyl R_(10a)R_(10b)NCOO—2-PyCO— 4-pyridyl R_(10a)R_(10b)NCOO— 2-PyCO— isobutenylR_(10a)R_(10b)NCOO— 2-PyCO— isopropyl R_(10a)R_(10b)NCOO— 2-PyCO—cyclopropyl R_(10a)R_(10b)NCOO— 2-PyCO— cyclobutyl R_(10a)R_(10b)NCOO—2-PyCO— cyclopentyl R_(10a)R_(10b)NCOO— 2-PyCO— phenylR_(10a)R_(10b)NCOO— 3-PyCO— 2-furyl R_(10a)R_(10b)NCOO— 3-PyCO— 3-furylR_(10a)R_(10b)NCOO— 3-PyCO— 2-thienyl R_(10a)R_(10b)NCOO— 3-PyCO—3-thienyl R_(10a)R_(10b)NCOO— 3-PyCO— 2-pyridyl R_(10a)R_(10b)NCOO—3-PyCO— 3-pyridyl R_(10a)R_(10b)NCOO— 3-PyCO— 4-pyridylR_(10a)R_(10b)NCOO— 3-PyCO— isobutenyl R_(10a)R_(10b)NCOO— 3-PyCO—isopropyl R_(10a)R_(10b)NCOO— 3-PyCO— cyclopropyl R_(10a)R_(10b)NCOO—3-PyCO— cyclobutyl R_(10a)R_(10b)NCOO— 3-PyCO— cyclopentylR_(10a)R_(10b)NCOO— 3-PyCO— phenyl R_(10a)R_(10b)NCOO— 4-PyCO— 2-furylR_(10a)R_(10b)NCOO— 4-PyCO— 3-furyl R_(10a)R_(10b)NCOO— 4-PyCO—2-thienyl R_(10a)R_(10b)NCOO— 4-PyCO— 3-thienyl R_(10a)R_(10b)NCOO—4-PyCO— 2-pyridyl R_(10a)R_(10b)NCOO— 4-PyCO— 3-pyridylR_(10a)R_(10b)NCOO— 4-PyCO— 4-pyridyl R_(10a)R_(10b)NCOO— 4-PyCO—isobutenyl R_(10a)R_(10b)NCOO— 4-PyCO— isopropyl R_(10a)R_(10b)NCOO—4-PyCO— cyclopropyl R_(10a)R_(10b)NCOO— 4-PyCO— cyclobutylR_(10a)R_(10b)NCOO— 4-PyCO— cyclopentyl R_(10a)R_(10b)NCOO— 4-PyCO—phenyl R_(10a)R_(10b)NCOO— C₄H₇CO— 2-furyl R_(10a)R_(10b)NCOO— C₄H₇CO—3-furyl R_(10a)R_(10b)NCOO— C₄H₇CO— 2-thienyl R_(10a)R_(10b)NCOO—C₄H₇CO— 3-thienyl R_(10a)R_(10b)NCOO— C₄H₇CO— 2-pyridylR_(10a)R_(10b)NCOO— C₄H₇CO— 3-pyridyl R_(10a)R_(10b)NCOO— C₄H₇CO—4-pyridyl R_(10a)R_(10b)NCOO— C₄H₇CO— isobutenyl R_(10a)R_(10b)NCOO—C₄H₇CO— isopropyl R_(10a)R_(10b)NCOO— C₄H₇CO— cyclopropylR_(10a)R_(10b)NCOO— C₄H₇CO— cyclobutyl R_(10a)R_(10b)NCOO— C₄H₇CO—cyclopentyl R_(10a)R_(10b)NCOO— C₄H₇CO— phenyl R_(10a)R_(10b)NCOO— EtOCO2-furyl R_(10a)R_(10b)NCOO— EtOCO 3-furyl R_(10a)R_(10b)NCOO— EtOCO—2-thienyl R_(10a)R_(10b)NCOO— EtOCO— 3-thienyl R_(10a)R_(10b)NCOO—EtOCO— 2-pyridyl R_(10a)R_(10b)NCOO— EtOCO— 3-pyridylR_(10a)R_(10b)NCOO— EtOCO— 4-pyridyl R_(10a)R_(10b)NCOO— EtOCO—isobutenyl R_(10a)R_(10b)NCOO— EtOCO— isopropyl R_(10a)R_(10b)NCOO—EtOCO— cyclopropyl R_(10a)R_(10b)NCOO— EtOCO— cyclobutylR_(10a)R_(10b)NCOO— EtOCO— cyclopentyl R_(10a)R_(10b)NCOO— EtOCO— phenylR_(10a)R_(10b)NCOO— ibueCO— 2-furyl R_(10a)R_(10b)NCOO— ibueCO— 3-furylR_(10a)R_(10b)NCOO— ibueCO— 2-thienyl R_(10a)R_(10b)NCOO— ibueCO—3-thienyl R_(10a)R_(10b)NCOO— ibueCO— 2-pyridyl R_(10a)R_(10b)NCOO—ibueCO— 3-pyridyl R_(10a)R_(10b)NCOO— ibueCO— 4-pyridylR_(10a)R_(10b)NCOO— ibueCO— isobutenyl R_(10a)R_(10b)NCOO— ibueCO—isopropyl R_(10a)R_(10b)NCOO— ibueCO— cyclopropyl R_(10a)R_(10b)NCOO—ibueCO— cyclobutyl R_(10a)R_(10b)NCOO— ibueCO— cyclopentylR_(10a)R_(10b)NCOO— ibueCO— phenyl R_(10a)R_(10b)NCOO— iBuCO— 2-furylR_(10a)R_(10b)NCOO— iBuCO— 3-furyl R_(10a)R_(10b)NCOO— iBuCO— 2-thienylR_(10a)R_(10b)NCOO— iBuCO— 3-thienyl R_(10a)R_(10b)NCOO— iBuCO—2-pyridyl R_(10a)R_(10b)NCOO— iBuCO— 3-pyridyl R_(10a)R_(10b)NCOO—iBuCO— 4-pyridyl R_(10a)R_(10b)NCOO— IBuCO— isobutenylR_(10a)R_(10b)NCOO— iBuCO— isopropyl R_(10a)R_(10b)NCOO— iBuCO—cyclopropyl R_(10a)R_(10b)NCOO— iBuCO— cyclobutyl R_(10a)R_(10b)NCOO—iBuCO— cyclopentyl R_(10a)R_(10b)NCOO— iBuCO— phenyl R_(10a)R_(10b)NCOO—iBuOCO— 2-fuiyI R_(10a)R_(10b)NCOO— iBuOCO— 3-furyl R_(10a)R_(10b)NCOO—iBuOCO— 2-thienyl R_(10a)R_(10b)NCOO— iBuOCO— 3-thienylR_(10a)R_(10b)NCOO— iBuOCO— 2-pyridyl R_(10a)R_(10b)NCOO— iBuOCO—3-pyridyl R_(10a)R_(10b)NCOO— iBuOCO— 4-pyridyl R_(10a)R_(10b)NCOO—iBuOCO— isobutenyl R_(10a)R_(10b)NCOO— iBuOCO— isopropylR_(10a)R_(10b)NCOO— iBuOCO— cyclopropyl R_(10a)R_(10b)NCOO— iBuOCO—cyclobutyl R_(10a)R_(10b)NCOO— iBuOCO— cyclopentyl R_(10a)R_(10b)NCOO—iBuOCO— phenyl R_(10a)R_(10b)NCOO— iPrOCO— 2-furyl R_(10a)R_(10b)NCOO—iPrOCO— 3-furyl R_(10a)R_(10b)NCOO— iPrOCO— 2-thienylR_(10a)R_(10b)NCOO— iPrOCO— 3-thienyl R_(10a)R_(10b)NCOO— iPrOCO—2-pyridyl R_(10a)R_(10b)NCOO— iPrOCO— 3-pyridyl R_(10a)R_(10b)NCOO—iPrOCO— 4-pyridyl R_(10a)R_(10b)NCOO— iPrOCO— isobutenylR_(10a)R_(10b)NCOO— iPrOCO— isopropyl R_(10a)R_(10b)NCOO— iPrOCO—cyclopropyl R_(10a)R_(10b)NCOO— iPrOCO— cyclobutyl R_(10a)R_(10b)NCOO—iPrOCO— cyclopentyl R_(10a)R_(10b)NCOO— iPrOCO— phenylR_(10a)R_(10b)NCOO— iPrOCO— 2-furyl R_(10a)R_(10b)NCOO— nPrOCO— 3-furylR_(10a)R_(10b)NCOO— nPrOCO— 2-thienyl R_(10a)R_(10b)NCOO— nPrOCO—3-thienyl R_(10a)R_(10b)NCOO— nPrOCO— 2-pyridyl R_(10a)R_(10b)NCOO—nPrOCO— 3-pyridyl R_(10a)R_(10b)NCOO— nPrOCO— 4-pyridylR_(10a)R_(10b)NCOO— nPrOCO— isobutenyl R_(10a)R_(10b)NCOO— nPrOCO—isopropyl R_(10a)R_(10b)NCOO— nPrOCO— cyclopropyl R_(10a)R_(10b)NCOO—nPrOCO— cyclobutyl R_(10a)R_(10b)NCOO— nPrOCO— cyclopentylR_(10a)R_(10b)NCOO— nPrOCO— phenyl R_(10a)R_(10b)NCOO— nPrCO— 2-furylR_(10a)R_(10b)NCOO— nPrCO— 3-furyl R_(10a)R_(10b)NCOO— nPrCO— 2-thienylR_(10a)R_(10b)NCOO— nPrCO— 3-thienyl R_(10a)R_(10b)NCOO— nPrCO—2-pyridyl R_(10a)R_(10b)NCOO— nPrCO— 3-pyridyl R_(10a)R_(10b)NCOO—nPrCO— 4-pyridyl R_(10a)R_(10b)NCOO— nPrCO— isobutenylR_(10a)R_(10b)NCOO— nPrCO— isopropyl R_(10a)R_(10b)NCOO— nPrCO—cyclopropyl R_(10a)R_(10b)NCOO— nPrCO— cyclobutyl R_(10a)R_(10b)NCOO—nPrCO— cyclopentyl R_(10a)R_(10b)NCOO— nPrCO— phenyl R_(10a)R_(10b)NCOO—

EXAMPLE 5

Following the processes described in Example 1 and elsewhere herein, thefollowing specific taxanes having structural formula 15 may be prepared,wherein R₇ is hydroxy and R₁₀ in each of the series (that is, each ofseries “A” through “K”) is as previously defined, including wherein R₁₀is R_(10a)R_(10b)NCOO— and one of R_(10a) and R_(10b) is hydrogen andthe other is (i) substituted or unsubstituted C₁ to C₈ alkyl such asmethyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, orhexyl; (ii) substituted or unsubstituted C₂ to C₈ alkenyl such asethenyl or straight, branched or cyclic propenyl, butenyl, pentenyl orhexenyl; (iii) substituted or unsubstituted C₂ to C₈ alkynyl such asethynyl or straight or branched propynyl, butynyl, pentynyl, or hexynyl;(iv) phenyl or substituted phenyl such as nitro, alkoxy orhalosubstituted phenyl, or (v) substituted or unsubstitutedheteroaromatic such as furyl, thienyl, or pyridyl. The substituents maybe those identified elsewhere herein for substituted hydrocarbyl. In oneembodiment, preferred R₁₀ substituents include R_(10a)R_(10b)NCOO—wherein one of R_(10a) and R_(10b) is hydrogen and the other is methyl,ethyl, or straight, branched or cyclic propyl. In another embodiment,preferred R₁₀ substituents include R_(10a)R_(10b)NCOO— wherein one ofR_(10a) and R_(10b) is hydrogen and the other is substituted methyl,ethyl, or straight, branched or cyclic propyl.

In the “A” series of compounds, X₁₀ is as otherwise as defined herein.Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl,or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl, pyridyl,phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “B” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a), is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “C” series of compounds, X₁₀ and R_(9a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(9a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “D” and “E” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the betastereochemical configuration.

In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “G” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “H” series of compounds, X₁₀ is as otherwise as defined herein.Preferably, heterocyclo is preferably substituted or unsubstitued furyl,thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstituedfuryl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl),R_(2a) is preferably substituted or unsubstitued furyl, thienyl,pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have the betastereochemical configuration.

In the “I” series of compounds, X₁₀ and R_(2a), are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “J” series of compounds, X₁₀ and R_(2a), are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

Any substituents of each of X₃, X₅, R₂, R₇, and R₉ may be hydrocarbyl orany of the heteroatom containing substituents selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

(15) Series X₅ X₃ R₁₀ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O H A2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O H A3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O H A4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈ alkyl A5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈ alkylA6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂to C₈ alkyl A7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkenyl A8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O H substituted C₂ to C₈ alkenyl A9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O H substituted C₂ to C₈alkynyl A11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkynyl A12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O H substituted C₂ to C₈ alkynyl B1 —COOX₁₀ heterocycloR_(10b)R_(10b)NCOO— R_(2a)COO— O H B2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O H B3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O H B4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B5 —COX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂ to C₈ alkylB6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂to C₈ alkyl B7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O Hsubstituted C₂ to C₈ alkenyl B8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O H substituted C₂ to C₈ alkenyl B9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O H substituted C₂ to C₈ alkenyl B10—COOX₁₀ optionally R_(10a)R_(10b)NOOO R_(2a)COO— O H substituted C₂ toC₈ alkynyl B11 —COX₁₀ optionally R_(10a)R_(10b)NOOO- R_(2a)COO— O Hsubstituted C₂ to C₈ alkynyl B12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O H substituted C₂ to C₈ alkynyl C1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H C2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— RgaCOO H substituted C₂ to C₈ alkyl C5—COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substitutedC₂ to C₈ alkyl C6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkyl C7 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenylC8 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl C10 —COOX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl C11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO—H substituted C₂ to C₈ alkynyl C12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynylD1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH H D2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH H D3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— OH H D4 —COOX₁₀ optionallyR_(10a)R_(10b)NOO- C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH H substituted C₂ to C₈ alkylD6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH H substituted C₂to C₈ alkyl D7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkenyl D8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH H substituted C₂ to C₈ alkenyl D9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₃H₅COO— OH H substituted C₂ to C₈ alkenyl D10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH H substituted C₂ toC₈ alkynyl D11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O OH E2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O OH E3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— O OH E4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkylE6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂to C₈ alkyl E7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkenyl E8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ to C₈ alkenyl E10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OH substituted C₂ toC₈ alkynyl E11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H F4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkylF5 —COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkyl F6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F7 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenylF8 —COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10 —COOX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl F11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₅ alkynylG1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH H G2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH H G3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— OH H G4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkyl G5 —COX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈alkyl G6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkyl G7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂to C₈ alkenyl G10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkynyl G11 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— OH H substituted C₂ to C₈ alkynyl G12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl H1—COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH H2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH H3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— C₆H₅COO— OH OH H4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H5 —COX₁₀optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkylH6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂to C₈ alkyl H7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkenyl H8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H9 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H10—COOX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OH substituted C₂ toC₈ alkynyl H11 —COX₁₀ optionally R_(10a)R_(10b)NCOO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkynyl H12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO—C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl I1 —COOX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O OH I2 —COX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O OH I3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— O OH I4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I5 —COX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈alkyl I6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkyl I7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂to C₈ alkenyl I10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkynyl I11 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— O OH substituted C₂ to C₈ alkynyl I12 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1—COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH J2 —COX₁₀heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH J3 —CONHX₁₀ heterocycloR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH J4 —COOX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkyl J5—COX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ toC₈ alkyl J6 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkyl J7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂to C₈ alkenyl J10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OHOH substituted C₂ to C₈ alkynyl J11 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J12—CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— OH OH substituted C₂to C₈ alkynyl K1 —COOX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH K3 —CONHX₁₀ heterocyclo R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH K4 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH C₂ to C₈ alkyl K5 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to alkyl K6 —CONHX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkylK7 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkenyl K8 —COX₁₀ optionally R_(10a)R_(10b)NCOO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K9 —CONHX₁₀optionally R_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂to C₈ alkenyl K10 —COOX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkynyl K11 —COX₁₀ optionallyR_(10a)R_(10b)NCOO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkynyl K12 —CONHX₁₀ optionally R_(10a)R_(10b)NCOO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkynyl

EXAMPLE 6 In Vitro Cytotoxicity Measured by the Cell Colony FormationAssay

Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovineserum and 100 units/mL penicillin and 100 g/mL streptomycin). The cellswere incubated in a CO₂ incubator at 37° C. for 5 h for attachment tothe bottom of Petri dishes. The compounds identified in Example 2 weremade up fresh in medium at ten times the final concentration, and then0.3 mL of this stock solution was added to the 2.7 mL of medium in thedish. The cells were then incubated with drugs for 72 h at 37° C. At theend of incubation the drug-containing media were decanted, the disheswere rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL offresh medium was added, and the dishes were returned to the incubatorfor colony formation. The cell colonies were counted using a colonycounter after incubation for 7 days. Cell survival was calculated andthe values of ID50 (the drug concentration producing 50% inhibition ofcolony formation) were determined for each tested compound.

IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 2600 <1 261627 2622 <1 2633 <10 2686 <1 2692 <1 2700 <1 2717 <1 2722 <1 2733 <102757 <1 2640 <1 2743 <1 6015 <10 6024 <1 6072 <1

1. A taxane having the formula:

R₁₀ is R_(10a)NHCOO— wherein R_(10a) is hydrocarbyl, substituted hydrocarbyl or heterocyclo; X₃ is heterocyclo, X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, Ac is acetyl, and Bz is benzoyl.
 2. The taxane of claim 1 wherein X₃ is furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl.
 3. The taxane of claim 1 wherein X₃ is oxazolyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, thiazolyl or isoxazolyl.
 4. The taxane of claim 2 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
 5. The taxane of any of claims 2-4 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, C₁-C₈ alkyl, or C₂-C₈ alkenyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl or C₂-C₈ alkenyl.
 6. The taxane of claim 5 wherein X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl.
 7. The taxane of claim 5 wherein R_(10a) is methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl.
 8. The taxane of claim 5 wherein R_(10a) is substituted or unsubstituted phenyl.
 9. A taxane having the formula:

R₉ is hydroxy or acyloxy; R₁₀ is R_(10a)R_(10b)NCOO— and R_(10a) and R_(10b) are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; X₃ is substituted or unsubstituted alkyl, alkenyl, or alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, Ac is acetyl, and Bz is benzoyl.
 10. The taxane of claim 9 wherein X₃ is furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl.
 11. The taxane of claim 9 wherein X₃ is oxazolyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl, thiazolyl or isoxazolyl.
 12. The taxane of claim 10 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
 13. The taxane of any of claims 10-12 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, C₁-C₈ alkyl, or C₂-C₈ alkenyl, or X₅ is —COOK₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl or C₂-C₈ alkenyl.
 14. The taxane of claim 13 wherein X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl.
 15. The taxane of claim 13 wherein R_(10a) is methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl.
 16. The taxane of claim 13 wherein R_(10a) is substituted or unsubstituted phenyl.
 17. A taxane having the formula:

R₁₀ is R_(10a)R_(10b)NCOO— and R_(10a) and R_(10b) are independently hydrogen, hydrocarbyl, substituted hydrocarbyl, or heterocyclo; R₁₄ is hydroxy; X₃ is substituted or unsubstituted alkyl, alkenyl, or alkynyl, or heterocyclo, wherein alkyl comprises at least two carbon atoms; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo, Ac is acetyl, and Bz is benzoyl.
 18. The taxane of claim 17 wherein X₃ is furyl, thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl.
 19. The taxane of claim 17 wherein X₃ is oxazolyl, pyrrolyl, indolyl, quinolinyl, isoquinoliriyl, thiazolyl or isoxazolyl.
 20. The taxane of claim 18 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.
 21. The taxane of any of claims 18-20 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, C₁-C₈ alkyl, or C₂-C₈ alkenyl, or X₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl or C₂-C₈ alkenyl.
 22. The taxane of claim 21 wherein X₃ is —COOX₁₀ and X₁₀ is substituted or unsubstittited methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl.
 23. The taxane of claim 21 wherein R_(10a) is methyl, ethyl, or straight, branched or cyclic propyl, butyl, pentyl, or hexyl.
 24. The taxane of claim 21 wherein R_(10a) is substituted or unsubstituted phenyl.
 25. A pharmaceutical composition comprising the taxane of any of claims 1, 9 or 17 and at least one pharmaceutically acceptable carrier.
 26. The composition of claim 25 wherein the composition is administered orally.
 27. The composition of claim 25 wherein the composition is administered parenterally.
 28. A method of inhibiting tumor growth in a mammal, said method comprising orally administering a therapeutically effective amount of a pharmaceutical composition comprising the taxane of any of claims 1, 9, or 17 and at least one pharmaceutically acceptable carrier.
 29. A taxane having the formula:

wherein R₁₀ is R_(10a)R_(10b)NCOO—; one of R_(10a) and R_(10b) is ethyl and the other is hydrogen; X₃ is isopropyl, cyclopropyl, cyclobutyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or p-nitrophenyL X₅ is —COOX₁₀ and X₁₀ is t-butyl; and Ac is acetyl.
 30. The taxane of claim 29 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl or 3-thienyl.
 31. The taxane of claim 29 wherein X₃ is 2-furyl or 2-thienyl.
 32. The taxane having the formula:

wherein R₁₀ is R_(10a)R_(10b)NCOO—; one of R_(10a) and R_(10b) is ethyl, phenyl or 3,4-difluoropheflyl and the other is hydrogen; X₃ is 2-furyl; X₅ is —COX₁₀ and X₁₀ is trans-propenyl: and Ac is acetyl. 